EFhd2, a Protein Linked to Alzheimer's Disease and Other Neurological Disorders.

Vega IE - Front Neurosci (2016)

Bottom Line:
Although, EFhd2 is more abundant in neurons, it is also found in other cell types.Recent studies demonstrated that EFhd2 has structural characteristics similar to amyloid proteins found in neurological disorders.These results suggest that EFhd2 may play an important role in the pathophysiology of neurodegenerative diseases.

Affiliation: Department of Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University Grand Rapids, MI, USA.

ABSTRACTEFhd2 is a conserved calcium binding protein linked to different neurological disorders and types of cancer. Although, EFhd2 is more abundant in neurons, it is also found in other cell types. The physiological function of this novel protein is still unclear, but it has been shown in vitro to play a role in calcium signaling, apoptosis, actin cytoskeleton, and regulation of synapse formation. Recently, EFhd2 was shown to promote cell motility by modulating the activity of Rac1, Cdc42, and RhoA. Although, EFhd2's role in promoting cell invasion and metastasis is of great interest in cancer biology, this review focusses on the evidence that links EFhd2 to Alzheimer's disease (AD) and other neurological disorders. Altered expression of EFhd2 has been documented in AD, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and schizophrenia, indicating that Efhd2 gene expression is regulated in response to neuropathological processes. However, the specific role that EFhd2 plays in the pathophysiology of neurological disorders is still poorly understood. Recent studies demonstrated that EFhd2 has structural characteristics similar to amyloid proteins found in neurological disorders. Moreover, EFhd2 co-aggregates and interacts with known neuropathological proteins, such as tau, C9orf72, and Lrrk2. These results suggest that EFhd2 may play an important role in the pathophysiology of neurodegenerative diseases. Therefore, the understanding of EFhd2's role in health and disease could lead to decipher molecular mechanisms that become activated in response to neuronal stress and degeneration.

Figure 1: Working hypothesis: EFhd2 role in neurodegeneration. (1) Activation: Pathological signals, such accumulation of Aβ oligomers, calcium influx, and neuroinflammation, lead to the activation of specific kinases, such as GSK3β and Cdk5/p25, and upregulation of gene expression. These kinases mediate the hyperphosphorylation of tau proteins and promote its release from the microtubules (MTs). Altered expression of Efhd2 gene leads to increase abundance of EFhd2 protein. (2) Oligomerization: The accumulation of EFhd2 proteins and its self-oligomerization properties could serve as a nucleation factor for hyperphosphorylated tau proteins, enhancing the kinetics of the formation of tau oligomers and/or neurofibrillary tangles at the somatodendritic compartment. Additionally, the accumulation of EFhd2 proteins affects kinesin-mediated fast axonal transport and promotes actin-bundling. (3) Toxicity: The accumulation of EFhd2 and tau oligomers leads to neuronal death and its release to the interstitial fluid, where are up-taken by neighboring neurons. Alternatively, EFhd2 could accelerate the transition from tau oligomers to neurofibrillary tangles (NFTs) as a neuroprotective mechanism, reducing the capacity of toxic tau transmission. Further studies are required to define the pathological role of EFhd2 in AD and other neurological disorders.

Mentions:
Further biochemical characterization of EFhd2 protein demonstrated that this novel protein has the molecular and structural features of amyloid proteins (Ferrer-Acosta et al., 2013b). In vitro studies showed that Thioflavin S (a dye that selectively binds to amyloid structures) binds recombinant EFhd2 protein, indicating that EFhd2 transition from a mostly helical and random coil structure to cross-beta-sheet (Ferrer-Acosta et al., 2013a,b). Amyloid proteins tend to form oligomers and filamentous structures. Electron microscopy analyses confirmed that EFhd2 forms filaments in vitro without the requirement of a nucleation factor (Congdon et al., 2008; Ferrer-Acosta et al., 2013b). Furthermore, the presence of calcium reduces EFhd2's ability to form filaments, and the coiled-coil domain was shown to be required for the formation of EFhd2 homodimers (Ferrer-Acosta et al., 2013b). These results indicated that formation of EFhd2 filaments could promote the association with pathological tau filaments. To test this hypothesis, immunohistological analyses of AD brain slices were performed. The results showed that EFhd2 co-localized with PHF1 (an antibody that recognized tau filaments) in the somatodendritic compartment, validating the association of EFhd2 with filamentous tau structures (Ferrer-Acosta et al., 2013b). Moreover, immune-gold electron microscopy showed that EFhd2 and tau, purified from AD brain, formed co-filaments (Ferrer-Acosta et al., 2013b). Moreover, in vitro protein–protein interaction assays demonstrated that EFhd2's coiled-coil domain is necessary for its association with tau proteins purified from brain extract derived from JNPL3 mice (Ferrer-Acosta et al., 2013b). Thus, it is plausible to hypothesize that formation of EFhd2 oligomers may serve as nucleation factor for tau oligomerization and, consequently, NFTs in AD and other tauopathies (Figure 1). Nevertheless, further studies are required to determine EFhd2's capability to enhance protein aggregation in tauopathy and other neurodegenerative disorders.

Figure 1: Working hypothesis: EFhd2 role in neurodegeneration. (1) Activation: Pathological signals, such accumulation of Aβ oligomers, calcium influx, and neuroinflammation, lead to the activation of specific kinases, such as GSK3β and Cdk5/p25, and upregulation of gene expression. These kinases mediate the hyperphosphorylation of tau proteins and promote its release from the microtubules (MTs). Altered expression of Efhd2 gene leads to increase abundance of EFhd2 protein. (2) Oligomerization: The accumulation of EFhd2 proteins and its self-oligomerization properties could serve as a nucleation factor for hyperphosphorylated tau proteins, enhancing the kinetics of the formation of tau oligomers and/or neurofibrillary tangles at the somatodendritic compartment. Additionally, the accumulation of EFhd2 proteins affects kinesin-mediated fast axonal transport and promotes actin-bundling. (3) Toxicity: The accumulation of EFhd2 and tau oligomers leads to neuronal death and its release to the interstitial fluid, where are up-taken by neighboring neurons. Alternatively, EFhd2 could accelerate the transition from tau oligomers to neurofibrillary tangles (NFTs) as a neuroprotective mechanism, reducing the capacity of toxic tau transmission. Further studies are required to define the pathological role of EFhd2 in AD and other neurological disorders.

Mentions:
Further biochemical characterization of EFhd2 protein demonstrated that this novel protein has the molecular and structural features of amyloid proteins (Ferrer-Acosta et al., 2013b). In vitro studies showed that Thioflavin S (a dye that selectively binds to amyloid structures) binds recombinant EFhd2 protein, indicating that EFhd2 transition from a mostly helical and random coil structure to cross-beta-sheet (Ferrer-Acosta et al., 2013a,b). Amyloid proteins tend to form oligomers and filamentous structures. Electron microscopy analyses confirmed that EFhd2 forms filaments in vitro without the requirement of a nucleation factor (Congdon et al., 2008; Ferrer-Acosta et al., 2013b). Furthermore, the presence of calcium reduces EFhd2's ability to form filaments, and the coiled-coil domain was shown to be required for the formation of EFhd2 homodimers (Ferrer-Acosta et al., 2013b). These results indicated that formation of EFhd2 filaments could promote the association with pathological tau filaments. To test this hypothesis, immunohistological analyses of AD brain slices were performed. The results showed that EFhd2 co-localized with PHF1 (an antibody that recognized tau filaments) in the somatodendritic compartment, validating the association of EFhd2 with filamentous tau structures (Ferrer-Acosta et al., 2013b). Moreover, immune-gold electron microscopy showed that EFhd2 and tau, purified from AD brain, formed co-filaments (Ferrer-Acosta et al., 2013b). Moreover, in vitro protein–protein interaction assays demonstrated that EFhd2's coiled-coil domain is necessary for its association with tau proteins purified from brain extract derived from JNPL3 mice (Ferrer-Acosta et al., 2013b). Thus, it is plausible to hypothesize that formation of EFhd2 oligomers may serve as nucleation factor for tau oligomerization and, consequently, NFTs in AD and other tauopathies (Figure 1). Nevertheless, further studies are required to determine EFhd2's capability to enhance protein aggregation in tauopathy and other neurodegenerative disorders.

Bottom Line:
Although, EFhd2 is more abundant in neurons, it is also found in other cell types.Recent studies demonstrated that EFhd2 has structural characteristics similar to amyloid proteins found in neurological disorders.These results suggest that EFhd2 may play an important role in the pathophysiology of neurodegenerative diseases.

Affiliation:
Department of Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University Grand Rapids, MI, USA.

ABSTRACTEFhd2 is a conserved calcium binding protein linked to different neurological disorders and types of cancer. Although, EFhd2 is more abundant in neurons, it is also found in other cell types. The physiological function of this novel protein is still unclear, but it has been shown in vitro to play a role in calcium signaling, apoptosis, actin cytoskeleton, and regulation of synapse formation. Recently, EFhd2 was shown to promote cell motility by modulating the activity of Rac1, Cdc42, and RhoA. Although, EFhd2's role in promoting cell invasion and metastasis is of great interest in cancer biology, this review focusses on the evidence that links EFhd2 to Alzheimer's disease (AD) and other neurological disorders. Altered expression of EFhd2 has been documented in AD, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and schizophrenia, indicating that Efhd2 gene expression is regulated in response to neuropathological processes. However, the specific role that EFhd2 plays in the pathophysiology of neurological disorders is still poorly understood. Recent studies demonstrated that EFhd2 has structural characteristics similar to amyloid proteins found in neurological disorders. Moreover, EFhd2 co-aggregates and interacts with known neuropathological proteins, such as tau, C9orf72, and Lrrk2. These results suggest that EFhd2 may play an important role in the pathophysiology of neurodegenerative diseases. Therefore, the understanding of EFhd2's role in health and disease could lead to decipher molecular mechanisms that become activated in response to neuronal stress and degeneration.